Alzheimer's disease (AD) is one of the major health problems in the US and of increasing importance as the proportion of elderly increases. Multiple survey and family studies have shown evidence for a genetic component consistent with a major gene. The overall purpose of this proposal is to identify genes involved in Alzheimer's disease (AD). As part of a multi- center cooperative study funded by NIMH (Diagnostic Centers for Psychiatric Linkage Studies), clinical data and DNA are being collected on 400 sibships with multiple cases of familial Alzheimer's disease (FAD). This effort represents a continuation of the ongoing collaboration to test the following hypotheses: 1) A major gene either singularly or interacting with other genes cause the common forms of FAD: Families will be genotyped for highly polymorphic markers at approximately 10cM intervals throughout the genome. This work will be divided between the 3 centers. Loci of reported significance such as the linkage to 19q in families with an older age-of-onset and chromosome 14 in families with an earlier age-of-onset will be prioritized in order to determine the importance of these genes in our families (82%) with age-of-onset greater than 65 years). In addition, families will be screened for known mutations in the amyloid beta protein precursor gene on chromosome 21; 2) FAD is a genetically heterogeneous disorder: To maximize our power to detect linkage and heterogeneity, linkage data will be analyzed using standard likelihood techniques with age-dependent penetrance as well as sib-pair and affected pedigree member approaches which do not require knowledge of a specific mode of inheritance. Computer simulations will be performed to determine the best analytic strategy that should be employed; 3) Once evidence for linkage is obtained, additional highly polymorphic markers and candidate genes in that chromosomal region will be typed. Our laboratories will develop additional highly polymorphic markers in regions of interest as required. Three centers will collaborate in this project; data will be routinely exchanged and, similar techniques will be used for genotyping and data analysis.